E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1 |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with Spinal Muscular Atrophy Type 1 |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Determine efficacy by demonstrating achievement of developmental milestone of sitting without support up to 18 months of age as defined by WHO Motor Developmental Milestones |
|
E.2.2 | Secondary objectives of the trial |
Determine efficacy based on survival at 14 months of age. Survival is defined by the avoidance of combined endpoint of either (a) death or (b) permanent ventilation which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via non invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation, so defined, is considered a surrogate for death. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with SMA Type 1 as determined by the diagnosis of SMA based on gene mutation analysis with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G>C)]
• Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion.
• Patients must have a swallowing evaluation test performed prior to administration of gene replacement therapy.
|
|
E.4 | Principal exclusion criteria |
• Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening
- Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and dosing with confirmatory oximetry reading
- Patients may be put on non-invasive ventilatory support for less than 12 hours per day at the discretion of their physician or trial staff.
• Use or requirement of non-invasive ventilatory support for 12 or more hours daily in the two weeks prior to dosing.
• Patient with signs of aspiration based on a swallowing test or whose weight-for-age falls below the 3rd percentile based on World Health Organization (WHO) Child Growth Standards [27] and is unwilling to use an alternative method to oral feeding.
• Participation in recent SMA treatment clinical study (with the exception of observational cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product, or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any time prior to screening for this study. Oral β-agonists must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable.
• Patient < 35 weeks gestational age at time of birth.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Proportion of symptomatic SMA Type 1 patients who are homozygous negative for SMN1 exon 7 and have two copies of SMN2 without the SMN2 genetic modifier that achieve the ability to sit without support for at least 10 seconds up to and including the 18 months of age trial visit. Sitting without support is defined by the World Health Organization Multicentre Growth Reference Trial (WHO MGRS), confirmed by video recording, as a patient who sits up straight with head erect for at least 10 seconds; child does not use arms or hands to balance body or support position.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Survival at 14 months of age amongst symptomatic SMA Type 1 patients who are homozygous negative for SMN1 exon 7 and have two copies of SMN2 without the SMN2 genetic modifier. Survival is defined by the avoidance of the combined endpoint of either (a) death or (b) permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via non‑invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation, so defined, is considered a surrogate for death.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open-label, single-arm, single-dose |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |